Blood coagulation is a process consisting of a complex interaction of various blood components (or factors) that eventually gives rise to a fibrin clot [Roberts et al. 2006]. Generally, the blood components, which participate in what has been referred to as the coagulation “cascade”, are enzymatically inactive proteins (proenzymes or zymogens) that are converted to proteolytic enzymes by the action of an activator (which itself is an activated clotting factor). Coagulation factors that have undergone such a conversion are generally referred to as “active factors”, and are designated by the addition of the letter “a” to the name of the coagulation factor (e.g. Factor VIIa). Initiation of the hemostatic process is mediated by the formation of a complex between tissue factor, exposed as a result of injury to the vessel wall, and Factor VIIa [Roberts et al. 2006]. This complex then converts Factors IX and X to their active forms. Factor Xa converts limited amounts of prothrombin to thrombin on the tissue factor-bearing cell. Thrombin activates platelets and Factors V and VIII into Factors Va and VIIIa, both cofactors in the further process leading to the full thrombin burst. This process includes generation of Factor Xa by Factor IXa (in complex with factor VIIIa) and occurs on the surface of activated platelets. Thrombin finally converts fibrinogen to fibrin resulting in formation of a fibrin clot. In recent years Factor VII and tissue factor have been found to be the main initiators of blood coagulation.
It is often desirable to stimulate or improve the coagulation competence in a subject to control bleeding disorders that have several causes such as clotting factor deficiencies (e.g. hemophilia A and B or deficiency of coagulation Factors XI or VII) or clotting factor inhibitors [Singh et al. 2007] and also to control excessive bleeding occurring in subjects with a normally functioning blood clotting cascade (no clotting factor deficiencies or inhibitors against any of the coagulation factors). Such bleeding may, for example, be caused by a defective platelet function, thrombocytopenia or von Willebrand's disease [Brace 2007]. Bleeding is also a major problem in connection with surgery and other forms of tissue damage [Vaslev et al. 2002, Hardy et al. 2005].
In order to control the bleeding for example in connection with surgery or trauma a multifaceted treatment of the bleeding is initiated, including the below examples of treatments which are performed either alone or in combination:                1. Surgical hemostatic techniques by diathermia, clamping, sutures or packaging,        2. Administration of blood products such as red blood cells (RBC), plasma, containing coagulation factors and platelets,        3. Endovascular treatment (coiling),        4. Local hemostatic compounds including fibrin glue, pads with thrombin and other coagulation factors, local injection of vasoconstrictors,        5. Pro-hemostatic pharmaceuticals such as recombinant factor VIIa, recombinant factor XIIIa, and factor concentrates either produced from human plasma or by recombinant technique for FVIII and FIX,        6. Antifibrinolytic pharmaceuticals such as aprotinin, tranexamic acid and others [Cheung et al. 2007].        
Pivotal for many of these medical treatments and procedures are the administration of allogenic blood products [Ferraris et al. 2007]. However, administration of allogenic blood products is associated with development of transfusion related complications such as:                a) intravascular hemolytic transfusion reaction,        b) delayed hemolytic transfusion reaction,        c) transfusion related acute lung injury (TRALI),        d) transfusion transmitted infections by virus (HTLV, HIV 1, 2, Hepatitis B, C, CMV) or bacteria,        e) transfusion associated graft versus host reaction (TA-GVHD),        f) posttransfusions purpura (PTP) [Stainsby et al. 2006].        
In addition, transfusion of allogenic blood products is also associated with immunomodulation and immunosuppression predisposing for the development of postoperative infections as reported in orthopedic, burn and colorectal surgery [Banbury et al. 2006, Jeschke et al. 2007, Milasiene et al. 2007]. Furthermore, it has been reported by several groups that administration of blood products is independently associated with an increase in development of multiorgan failure [Zallen et al 1999] and mortality [Herbert et al. 1999, Engoren et al. 2002, Karkouti et al. 2004]. In fact, administration of red blood cells to patients undergoing surgical revascularization of coronary arteries dose-dependently is associated with increased 5 year mortality [Engoren et al. 2002]. In addition, transfusion of blood products may result in microchimerism with the immunocompetent donor leukocytes surviving indefinitely in the recipient [Reed et al. 2007].
Accordingly, in treatment of bleeding episodes, e.g. due to trauma, surgery or other medical treatments, the above-mentioned hazards of allogenic blood transfusion and the increasing shortage of allogenic blood donors and hence shortage of blood products calls for new options for pro-hemostatic treatments that improve the subjects clotting ability and hence reduce the bleeding and the need for allogenic blood transfusion in these subjects, without compromising the safety of the recipient.
In order to reduce blood loss locally, vasoconstrictors such as adrenaline and noradrenaline have been used either alone or in combination with any of the above-mentioned treatment alternatives. By local administration of vasoconstrictors the peripheral blood vessels are constricted whereby blood loss is reduced. By local administration, the systemic effects normally associated with vasoconstrictors are avoided, such as, for example, elevated systemic blood pressure and thus increased blood loss through open vessels.
Several reports exist on the use of vasoconstrictors as local hemostatic agents. For example in US 2007/0073210 is disclosed a wound dressing comprising a vasoconstrictive medicinal substance, such as adrenaline, as a ready to use product for local treatment of bleeding wounds.
Local administration of vasoconstrictors, such as adrenaline and noradrenaline, to a hemodialysis site in order to reduce complications associated with hemodialysis therapy is disclosed in US20050075597.
In WO0182937 compositions of intermacromolecular complexes such as, e.g. polyether, polyacids and polyalkylene and methods for making and using such compositions in reducing post-surgical bleeding is described. The application further describes the incorporation of vasoconstrictors in these compositions in order to have a local drug delivery at a surgical site.
Furthermore, the use of vasoconstrictors in a method to control gastrointestinal bleeding when injected directly into the peritoneal cavity or intragastrically is described U.S. Pat. No. 4,337,573. By this method, a local effect is obtained without any unwanted systemic effects because the vasoconstrictors are absorbed into the portal system and inactivated before entering systemic circulation.
In all these cited reports use is made of the vasoconstrictor effects of e.g. adrenaline and noradrenaline on the peripheral blood vessels by local administration in order to reduce bleeding.